Atopic Dermatitis (AD) is the most common chronic relapsing inflammatory skin disease with increasing global incidence, thus constituting a serious public health concern. Currently there is no well-delineated cause or effective cure for this skin condition. Therefore there is a vital need for additional mechanistic studies and for the development of new and effective experimental tools to examine the etiology and progression of this skin disease. Our data suggest that the transcription factor p63, specifically the keratinocyte-enriched ?Np63 isoforms, may contribute to the pathogenesis of AD. ?Np63 not only plays a critical role in morphogenesis and differentiation of the skin, but when amplified and/or overexpressed, it contributes to pathological conditions including inflammatory diseases and squamous cancers. We find that overexpression of ?Np63 in transgenic mice (?Np63BG) results in a distinct skin phenotype that shares many of the crucial histological, pathological and molecular features associated with human AD skin lesions. Importantly, this observation is in good agreement with published reports showing elevated p63 expression levels in lesional skin of human AD patients. Interestingly, the skin phenotype of the ?Np63BG animals is also associated with increased expression of cytokines and chemokines that have been implicated in the pathogenesis of AD, including the itch inducing cytokine IL-31 and IL-31RA, two p63-target genes. Thus, examining the biological functions of p63 and identifying additional target genes that may contribute to the development of AD, will lead to a better understanding of the molecular attributes of this disease. However, our current knowledge regarding the contribution of p63 to the development of AD remains sparse. To address the knowledge gaps, we will utilize AD patient samples together with a novel transgenic mouse model to answer two key questions. First, given the previously published study demonstrating elevated p63 transcript levels in AD lesioned skin, and the link between IL-31 and IL-31RA in the induction of pruritis, are the protein expression levels of p63, specifically ?Np63, and IL-31/IL-31RA elevated in lesional skin samples of patients with AD? Second, are there additional ?Np63 target genes, which also contribute to the AD phenotype in the ?Np63BG animals? By performing chromatin-immunoprecipitation followed by deep sequencing (ChIP-seq) in vivo, we plan to identify ?Np63-dependent genes and regulatory pathways that contribute to the etiology of AD. Such molecular studies have not been performed to date in any AD mouse model. Collectively, the information gleaned from these studies has the potential to significantly enhance our understanding of the underlying pathogenesis of AD including the molecular features associated with itch-induction, and thereby offer new and effective strategies in the treatment of this inflammatory skin disease in the long term.